Ovarian expression of alpha (1)- and beta (2)-adrenoceptors and p75 neurotrophin receptors in rats with steroid-induced polycystic ovaries Luigi Manni a,b , Agneta Holm7ng a , Thomas Lundeberg c , Luigi Aloe b , Elisabet Stener-Victorin a,d,e, T a Cardiovascular Institute and Wallenberg Laboratory, Sahlgrenska Academy, Go ¨teborg University, Go ¨teborg SE-413 45, Sweden b Institute of Neurobiology and Molecular Medicine (CNR), Rome, Italy c Rehabilitation Medicine, Karolinska Hospital, Stockholm SE-171 77, Sweden d Department of Obstetrics and Gynaecology, Sahlgrenska University Hospital, Sahlgrenska, Go ¨teborg SE-413 45, Sweden e Institute of Occupational Therapy and Physical Therapy, Sahlgrenska Academy, Go ¨teborg University, Go ¨teborg SE-405 30, Sweden Received 4 December 2004; received in revised form 10 January 2005; accepted 16 January 2005 Abstract Polycystic ovary syndrome (PCOS) is the main cause of infertility in women. Despite extensive research aimed at identifying the pathogenetic mechanism underlying this condition, the aetiology of the disease is still unknown. Evidence from studies on women with PCOS and on an experimental rat polycystic ovary (PCO) model suggests that the sympathetic regulatory drive to the ovary may be unbalanced. The present study was designed to investigate this hypothesis. Accordingly, we used the well-defined rat PCO model, where PCO is induced by a single intramuscular (i.m.) injection of estradiol valerate (EV), and compared the model with oil-injected controls. We studied the ovarian expression of the a 1 - and h 2 -adrenoceptors (ARs), the neurotrophin receptor p75 (p75 NTR ), and the sympathetic marker tyrosine hydroxylase (TH) at two time points: 30 and 60 days after EV injection. Our data demonstrate for the first time that all of the a 1 -AR subtypes are expressed in normal rat ovaries at both the mRNA and the protein levels. Furthermore, the expression of the a 1 -AR subtypes was differentially modulated in a time- and subtype-dependent manner in rats with EV-induced PCO. The ovaries in rats with steroid-induced PCO are characterised by an early overexpression of these molecules and p75 NTR , while the h 2 -AR was downregulated. An increase in the expression of ovarian TH after EV injection was also detected, suggesting a structural and functional remodelling of ovarian sympathetic innervation in PCO rats. Our evidence strongly indicates that the role of the sympathetic nervous system is crucial in the pathogenesis of EV-induced PCO. Overall, our findings suggest that therapeutical approaches aimed at down-regulating the sympathetic tone to the ovary could be useful in the prevention and clinical treatment of PCOS. D 2005 Elsevier B.V. All rights reserved. Keywords: Polycystic ovary syndrome; Polycystic ovaries; Sympathetic activity; Alpha-adrenoceptors; Beta-adrenoceptors; NGF; p75 NTR ; Anovulation 1. Introduction Polycystic ovary syndrome (PCOS) is recognised as the primary cause of infertility in women. It is a complex disease, characterised by ovulatory failure, hyperandrogen- ism, variable levels of gonadotropins, and large cystic follicles (Tsilchorozidou et al., 2004). Women with PCOS also have a higher risk of developing hypertension and insulin resistance. The precise aetiology of the disease is so far still unknown, but there are indications that human PCOS is associated with hyperactivity in the sympathetic nervous system. Findings that support the involvement of the sympathetic nervous system in the pathophysiology of 1566-0702/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2005.01.004 T Corresponding author. Cardiovascular Institute, Wallenberg Laboratory, Sahlgrenska University Hospital, The Sahlgrenska Academy at Go ¨teborg University, Go ¨teborg SE-413 45, Sweden. Tel.: +46 317735724; fax: +46 31 823762. E-mail address: elisabet.stener-victorin@fhs.gu.se (E. Stener-Victorin). Autonomic Neuroscience: Basic and Clinical 118 (2005) 79– 87 www.elsevier.com/locate/autneu